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Stable liquid formulation of AMG 416 (etelcalcetide)

a liquid formulation and stable technology, applied in the field of liquid formulation, can solve the problems of disulfide bonds, peptides in general, and peptides containing disulfide bonds, which have only moderate or poor stability in aqueous solution, and can be unstabl

Active Publication Date: 2017-11-21
AMGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therapeutic peptides pose a number of challenges with respect to their formulation.
Peptides in general, and particularly those that contain a disulfide bond, typically have only moderate or poor stability in aqueous solution.
Disulfide bonds can be unstable even under quite mild conditions (close to neutral pH).
In addition, disulfide containing peptides that are not cyclic are particularly prone to dimer formation.
A lyophilized formulation of a therapeutic peptide has the advantage of providing stability for long periods of time, but is less convenient to use as it requires the addition of one or more diluents and there is the potential risk for errors due to the use of an improper type or amount of diluent, as well as risk of contamination.
In addition, the lyophilization process is time consuming and costly.

Method used

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  • Stable liquid formulation of AMG 416 (etelcalcetide)
  • Stable liquid formulation of AMG 416 (etelcalcetide)
  • Stable liquid formulation of AMG 416 (etelcalcetide)

Examples

Experimental program
Comparison scheme
Effect test

example 1

Solubility of AMG 416 in Succinate Buffered Saline

[0087]In this study, the solubility of AMG 416 in succinate buffered-saline was investigated. AMG 416 HCl (103 mg powder, 80 mg peptide) was dissolved in 200 μL of sodium succinate buffered saline (25 mM succinate, 0.9% saline, pH 4.5). After briefly vortexing, a clear solution was obtained with a nominal concentration of 400 mg / mL. Because expansion of the solution volume was not determined, the solubility of AMG 416 can be conservatively stated as at least 200 mg / mL. Although the maximal solubility was not determined in this experiment, AMG 416 is soluble in pH 4.5 succinate buffered saline to concentrations of at least 200 mg / mL.

example 2

Concentration Dependent Stability Study

[0088]In this study, the stability of AMG 416 over a range of concentrations in succinate-buffered saline (pH 4.5) was investigated. The solution of 200 mg / mL AMG 416 from Example 1, supra, was diluted further with 200 μL of succinate-buffered saline (pH 4.5) to a nominal concentration of 200 mg / mL, which was serially diluted with succinate-buffered saline (pH 4.5) to 66, 20, 6.7, 2.2 and 0.67 mg / mL. The samples were kept at room temperature (i.e., about 25° C.) and aliquots were analyzed by HPLC at intervals up to 29 days. A second series of AMG 416 samples covering the concentration range 20 to 0.67 mg / mL were incubated at 40° C. and analyzed in the same manner.

[0089]The purity at the 29-day time point for samples at room temperature and 40° C. is provided in Tables 1 and 2, respectively. The results provide a stability profile of AMG 416 as a function of concentration and temperature.

[0090]

TABLE 1RT Stability of AMG 416 in 25 mM succinate-bu...

example 3

Stability of Liquid Formulations of AMG 416 Over Range of pH

[0098]In this study, the stability of liquid formulations of AMG 416, at a concentration of 10 mg / mL, was determined over a range of pH in succinate-buffered saline. AMG 416 HCl (257 mg powder) was dissolved in 20 ml of pH 4.5 succinate buffered saline to provide 10.0 mg / ml peptide concentration (adjusted for peptide content of powder). The solution was divided evenly into five 4 mL portions which were adjusted to pH 2, 3, 4, 5 and 6, respectively, with NaOH and HCl as needed. Three 1 mL solutions were aliquoted from each portion and incubated at 2-8° C., room temperature (about 25° C.), and 40° C., respectively. The remaining 1 mL solution in each aliquot was diluted with pH 4.5 succinate buffered saline to 4 mL of 2.5 mg / mL peptide concentration, pH adjusted, and incubated in the same manner. Samples were retrieved according to schedule and diluted with deionized water to 1.0 mg / mL for HPLC analysis.

[0099]The purity at th...

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Abstract

A liquid formulation comprising a peptide agonist of the calcium sensing receptor and method of preparing and using the formulation are provided.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a U.S. National Stage of International Patent Application No. PCT / US2014 / 044622, filed Jun. 27, 2014, which claims the benefit of U.S. Provisional Application No. 61 / 840,618, filed Jun. 28, 2013, the contents of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION[0002]The present disclosure relates to a liquid formulation comprising a peptide agonist of the calcium sensing receptor, particularly to such a formulation that remains stable after storage for an extended period. The disclosure is also directed to methods of preparing and using the formulation.BACKGROUND OF THE INVENTION[0003]A variety of compounds having activity for lowering parathyroid hormone levels have been described. See International Publication No. WO 2011 / 014707. In one embodiment, the compound may be represented as follows:[0004]The main chain has 7 amino acids, all in the D-configuration and the side-chain cysteine...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K47/12C07K7/00A61K9/00A61K31/785A61K33/04A61K45/06A61K31/663C07K7/06A61K38/08A61K38/00A61K9/08A61K31/135A61K31/59
CPCA61K9/08A61K47/12A61K38/08A61K9/0019A61P3/00A61P3/14A61P43/00A61P5/00A61P5/18F01D15/10F04D25/0606
Inventor MACLEAN, DEREKYIN, QUN
Owner AMGEN INC
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